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Article: Activating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia

TitleActivating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia
Authors
Issue Date2017
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
Citation
Human Molecular Genetics, 2017, v. 26 n. 23, p. 4572-4587 How to Cite?
AbstractBone remodeling is a balanced process between bone synthesis and degradation, maintaining homeostasis and a constant bone mass in adult life. Imbalance will lead to conditions such as osteoporosis or hyperostosis. Osteoblasts build bone, becoming embedded in bone matrix as mature osteocytes. Osteocytes have a role in sensing and translating mechanical loads into biochemical signals, regulating the differentiation and activity of osteoblasts residing at the bone surface through the secretion of Sclerostin (SOST), an inhibitor of WNT signaling. Excessive mechanical load can lead to activation of cellular stress responses altering cell behavior and differentiation. The unfolded protein response (UPR) is a shared pathway utilized by cells to cope with stress stimuli. We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the combined outcome is generalized hyperostosis. A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA). As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion. Thus, therapeutic agents ameliorating protein folding or the UPR can be considered as a potential therapeutic treatment.
Persistent Identifierhttp://hdl.handle.net/10722/244668
ISSN
2017 Impact Factor: 4.902
2015 SCImago Journal Rankings: 4.288

 

DC FieldValueLanguage
dc.contributor.authorChan, WCW-
dc.contributor.authorTsang, KY-
dc.contributor.authorCheng, YW-
dc.contributor.authorNg, VCW-
dc.contributor.authorCheung, KMC-
dc.contributor.authorTan, Z-
dc.contributor.authorBoot-Handford, R-
dc.contributor.authorBoyde, A-
dc.contributor.authorCheah, KSE-
dc.contributor.authorChan, D-
dc.date.accessioned2017-09-18T01:56:52Z-
dc.date.available2017-09-18T01:56:52Z-
dc.date.issued2017-
dc.identifier.citationHuman Molecular Genetics, 2017, v. 26 n. 23, p. 4572-4587-
dc.identifier.issn0964-6906-
dc.identifier.urihttp://hdl.handle.net/10722/244668-
dc.description.abstractBone remodeling is a balanced process between bone synthesis and degradation, maintaining homeostasis and a constant bone mass in adult life. Imbalance will lead to conditions such as osteoporosis or hyperostosis. Osteoblasts build bone, becoming embedded in bone matrix as mature osteocytes. Osteocytes have a role in sensing and translating mechanical loads into biochemical signals, regulating the differentiation and activity of osteoblasts residing at the bone surface through the secretion of Sclerostin (SOST), an inhibitor of WNT signaling. Excessive mechanical load can lead to activation of cellular stress responses altering cell behavior and differentiation. The unfolded protein response (UPR) is a shared pathway utilized by cells to cope with stress stimuli. We showed that in a transgenic mouse model, activation of the UPR in early differentiating osteocytes delays maturation, maintaining active bone synthesis. In addition, expression of SOST is delayed or suppressed; resulting in active WNT signaling and enhanced periosteal bone formation, and the combined outcome is generalized hyperostosis. A clear relationship between the activation of the unfolded protein response was established and the onset of hyperostosis that can be suppressed with a chemical chaperone, sodium 4-phenobutyrate (4-PBA). As the phenotype is highly consistent with craniodiaphyseal dysplasia (CDD; OMIM 122860), we propose activation of the UPR could be part of the disease mechanism for CDD patients as these patients are heterozygous for SOST mutations that impair protein folding and secretion. Thus, therapeutic agents ameliorating protein folding or the UPR can be considered as a potential therapeutic treatment.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/-
dc.relation.ispartofHuman Molecular Genetics-
dc.rightsPre-print: Journal Title] ©: [year] [owner as specified on the article] Published by Oxford University Press [on behalf of xxxxxx]. All rights reserved. Pre-print (Once an article is published, preprint notice should be amended to): This is an electronic version of an article published in [include the complete citation information for the final version of the Article as published in the print edition of the Journal.] Post-print: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in [insert journal title] following peer review. The definitive publisher-authenticated version [insert complete citation information here] is available online at: xxxxxxx [insert URL that the author will receive upon publication here]. -
dc.titleActivating the unfolded protein response in osteocytes causes hyperostosis consistent with craniodiaphyseal dysplasia-
dc.typeArticle-
dc.identifier.emailChan, WCW: cwilson@hkucc.hku.hk-
dc.identifier.emailTsang, KY: kytsang@hku.hk-
dc.identifier.emailNg, VCW: vcwng@hkucc.hku.hk-
dc.identifier.emailCheung, KMC: cheungmc@hku.hk-
dc.identifier.emailTan, Z: tanzj@hku.hk-
dc.identifier.emailCheah, KSE: hrmbdkc@hku.hk-
dc.identifier.emailChan, D: chand@hku.hk-
dc.identifier.authorityCheung, KMC=rp00387-
dc.identifier.authorityCheah, KSE=rp00342-
dc.identifier.authorityChan, D=rp00540-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1093/hmg/ddx339-
dc.identifier.hkuros277817-
dc.identifier.volume26-
dc.identifier.issue23-
dc.identifier.spage4572-
dc.identifier.epage4587-
dc.publisher.placeUnited Kingdom-

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